Process for preparing pan-cdk inhibitors of the formula (i), and intermediates in the preparation

ABSTRACT

The invention relates to a novel process for the preparation of pan-CDK inhibitors of the formula (I), and intermediates of the preparation.

The invention relates to a novel process for the preparation of pan-CDKinhibitors of the formula (I), and to intermediates of the preparation.

The novel process relates to compounds of the formula (I), in particularthe compound(2R,3R)-3-{[2-{[4-(S-cyclopropylsulphonimidoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]oxy}butan-2-ol(compound A), which develop their anti-tumour activity via a cytotoxicmechanism.

A preparation process for a compound of the general formula (I) has nowbeen found,

in whichR⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring,which is suitable for a scale-up and overcomes the disadvantages of thepreparation processes of the prior art for this substance class.

This preparation process is particularly suitable for the compound A

The application is based on the following definitions:

C₁-C₆-alkyl

A C₁-C₆-alkyl group is to be understood in each case as meaning astraight-chain or branched alkyl radical, such as, for example, amethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl or a hexyl radical.

C₃-C₇-cycloalkyl

A C₃-C₇-cycloalkyl ring is to be understood as meaning a cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or a cycloheptyl ring.

Compounds of the general formula (I), in particular also the compound Aand processes for their preparation are disclosed in WO2010/046035A1,the disclosure of which forms the closest prior art.

The process according to WO2010/046035A1 is a 10-stage convergentprocess with an overall yield for the longest sequence of ca. 7%.

The process according to WO2010/046035A1 involves at least one of thefollowing steps:

-   a) Oxidation of a nitrophenyl-sulphide of the formula (I-1) to give    the nitrophenyl-sulphoxide of the formula (I-2).

-   b₁) Direct imination of the nitrophenyl-sulphoxide of the formula    (I-2) to give a trifluoroacetate-protected nitrophenyl-sulphoximine    of the formula (I-3).

-   b₂) Imination of the nitrophenyl-sulphoxide of the formula (I-2) to    give a nitrophenyl-sulphoximine of the formula (I-11) and subsequent    insertion of the protective group to give a    trifluoroacetate-protected nitrophenyl-sulphoximine of the formula    (I-3).

-   c) Reduction of the compound of the formula (I-3) to give a compound    of the formula (I-4)

-   d) Functionalization of the 4-position of    2,4-dichloro-5-iodopyrimidine by reaction with a mono-protected diol    of the formula (I-5) to form a protected hydroxyalkoxypyrimidine of    the formula (I-6).

-   e) Preparation of the protected 5-CF₃ intermediate (I-7).

-   f) Coupling of the compounds of the formula (I-7) and (I-4) to give    a doubly protected anilinopyrimidine of the formula (I-8).

-   g) Cleaving off of the protective group (PG) to form a singly    protected anilinopyrimidine (I-9).

-   h) Cleaving off of the protective group on the sulphoximine to form    compounds of the formula (I).

where in WO2010/046035A1R¹ is a methyl, ethyl, propyl or isopropyl group, andR² and R³ independently of one another are hydrogen, a methyl or ethylgroup, andR⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring.

The diastereomers of the formula I were separated by means ofpreparative chromatography. The experimental details are given inWO2010/046035A1.

For the compound A, in WO2010/046035A1, the following conditions weredisclosed for the individual synthesis steps:

Preparation of the Intermediates 1-cyclopropylsulphanyl-4-nitrobenzene(I-1-A)

Cyclopropanethiol in THF/diethyl ether was admixed in portions withsodium hydride and stirred at room temperature. 1-Fluoro-4-nitrobenzenewas then added in portions. The mixture was stirred for 2 hours at 40°C. After cooling, the mixture was added to water and extracted withbenzene (3×). The combined organic phases were concentrated byevaporation and the residue was purified by chromatography(hexane/acetic ester 95:5). (Yield: 61%).

(RS)-1-cyclopropanesulphinyl-4-nitrobenzene (I-2-A)

1-Cyclopropylsulphanyl-4-nitrobenzene in acetonitrile was admixed withiron(III) chloride and stirred at room temperature. Periodic acid wasthen added in portions. The mixture was stirred for 30 minutes and thenadded, with stirring, to a cooled, saturated sodium thiosulphatesolution. Extraction was carried out with acetic ester (2×). Thecombined organic phases were dried (Na₂SO₄), filtered and concentratedby evaporation. The residue obtained was purified by means ofchromatography (hexane/acetic ester 1:1) (yield: 76%).

(RS)-S-cyclopropyl-S-(4-nitrophenyl)-N-(trifluoroacetyl)sulphoximide(I-3-A)

A suspension of (RS)-1-cyclopropanesulphinyl-4-nitrobenzene,trifluoroacetamide, iodobenzene diacetate and magnesium oxide in DCM wasadmixed, under argon, with rhodium(II) acetate dimer and stirredovernight at room temperature. The mixture was filtered off with suctionover Celite and concentrated by evaporation. The remaining residue waspurified by means of chromatography (hexane/acetic ester 2:1) (yield:78%).

(RS)-S-(4-aminophenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximide(I-4-A)

A solution of(RS)-S-cyclopropyl-S-(4-nitrophenyl)-N-(trifluoroacetyl)sulphoximide inethanol and THF was admixed with palladium on carbon and hydrogenatedfor 1 hour under atmospheric pressure at 25° C. Palladium on carbon wasadded again and the mixture was hydrogenated for a further 4.5 hours atatmospheric pressure. The mixture was filtered, the filtrate was againadmixed with palladium on carbon and finally hydrogenated for 45minutes. The mixture was filtered and concentrated by evaporation(yield: 93%).

(2R,3R)-3-benzyloxybutan-2-ol (I-5-A)

A solution of (2R,3R)-butane-2,3-diol in THF was admixed at roomtemperature with potassium tert-butylate and the mixture was refluxedfor 15 minutes. The mixture was cooled to ca. 50° C. and admixed withbenzyl bromide. The mixture was refluxed for 3 hours, then stirredovernight at room temperature. The mixture was diluted with acetic esterand sodium chloride solution and then washed with 1 N hydrogen chloridesolution (1×) and sodium chloride solution (2×). The organic phase wasdried (Na₂SO₄), filtered and concentrated by evaporation. The residueobtained was purified by means of chromatography (hexane/acetic ester1:1) (yield: 43%).

4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-iodopyrimidine(I-6-A)

(2R,3R)-3-Benzyloxybutan-2-ol in diethyl ether were admixed with sodiumhydride in portions at 0° C. with stirring. After 10 minutes, the icebath was removed and the mixture was stirred for a further 3 minutes atroom temperature. The suspension formed was added, at 0° C., to asolution of 2,4-dichloro-5-iodopyrimidine. The mixture was stirred for 4hours at 40° C. and then admixed with dilute sodium chloride solution.The mixture was extracted with acetic ester (2×). The combined organicphases were dried (Na₂SO₄), filtered and concentrated by evaporation.The resulting residue was purified by means of chromatography(hexane/acetic ester 4:1) (yield: 41%).

4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-trifluoromethylpyrimidine(I-7-A)

A solution of4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-iodopyrimidine in NMPand THF was admixed at room temperature with stirring with copper(I)iodide, potassium fluoride and (trifluoromethyl)trimethylsilane. Themixture was stirred for 5.5 hours at 80° C. After cooling, the mixturewas added to dilute sodium chloride solution and extracted with aceticester (2×). The combined organic phases were dried (Na₂SO₄), filteredand concentrated by evaporation. The residue obtained was purified bymeans of chromatography (hexane/acetic ester 4:1) (yield: 54%).

(RS)-S-(4-{[4-{[(1R,2R)-2-(benzyloxy)-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximide(I-8-A)

4-((1R,2R)-2-benzyloxy-1-methylpropoxy)-2-chloro-5-trifluoromethylpyrimidineand (RS)-S-(4-aminophenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximidein acetonitrile were admixed with a 4N solution of hydrogen chloride indioxane and stirred for 5 hours at 80° C. After cooling, the mixture wasdiluted with acetic ester and washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried(Na₂SO₄), filtered and concentrated by evaporation. The resultingresidue was purified by means of chromatography (hexane/acetic ester4:1) (yield: 56%).

(RS)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-N-(trifluoroacetyl)sulphoximide(I-9-A)

A solution of(RS)-S-(4-{[4-{[(1R,2R)-2-(benzyloxy)-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulphoximidein ethanol was admixed with palladium on carbon (10%) and hydrogenatedunder atmospheric pressure at room temperature. The mixture was filteredand concentrated by evaporation (yield: 79%).

Preparation of the Compound A

(RS)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-N-(trifluoroacetyl)sulphoximidein 35 ml of methanol were admixed with potassium carbonate and stirredfor 1.5 hours at room temperature. The mixture was diluted withsaturated sodium chloride solution and extracted with acetic ester (3×).The combined organic phases were dried (Na₂SO₄), filtered andconcentrated by evaporation.

The diastereomer mixture was separated into the pure stereoisomers bymeans of preparative HPLC:

Column: Chiralpak IA 5μ 250×30 mm Eluents: Hexane/ethanol 8:2

Flow: 40.0 ml/min

Detector: UV 254 nm

Temperature: Room temperatureRetention time: 10.8-13.4 min; stereoisomer 1

-   -   13.6-18.5 min; stereoisomer 2 (compound A)

This preparation of the compound of the formula (I) according toWO2010/046035A1 is unsuitable for a production process.

The most critical points are

-   -   The majority of the intermediates are purified by means of        chromatography. This is expensive and complex on a larger scale.    -   The starting material (I-1) was prepared from cyclopropyl        sulphide, which is not commercially available in large amounts.    -   A racemic oxidation method was used for the preparation of        (I-2). The stereoisomers therefore have to be separated by means        of chromatography at the end of the synthesis. Since the        separation only takes place at the end of the synthesis, the        overall yield for the synthesis sequence is drastically reduced.    -   In the preparation of (I-3), large amounts of rhodium(II)        acetate dimer are used. This is expensive and the rhodium has to        be removed so that there is no contamination in the active        ingredient. Iodobenzene diacetate is unsuitable for a scale-up        since it is not very available in large amounts and it is a        potential explosive material.    -   The alternative access to (I-3) via (I-2) and (I-2/3) is not        easy to carry out for safety reasons since toxic and explosive        substances such as sodium azide or        o-mesitylenesulphonylhydroxylamine (MSH) are used.    -   The synthesis of (I-5-A) is not selective since double        alkylation also occurs. The yield is therefore only 43%.    -   The sequence (I-6) to (I-7) is not convergent since the        trifluoromethyl group is not already entrained in the pyrimidine        building block. The yields of both steps is poor. Since the        conversions proceed with the formation of many secondary        components, it is additionally necessary to carry out        chromatography, which is complex.    -   Intermediate (I-8) is produced as an oil which can only be        cleaned by means of chromatography. On an industrial scale, the        oil can only be handled with difficulty and the storage        stability is poor compared to a solid.    -   In stage (I-9), the diastereomers are separated by preparative        methods. This is very complex and expensive. Moreover, much of        the overall yield is lost since the separation is only carried        out in the last synthesis stage.

These aspects have to be reworked and/or optimized in the course ofexpanding the synthesis to a multi-g or kg scale.

It was therefore an object of the present invention to provide a processfor the pan-CDK inhibitors of the general formula (I), in particular forcompound A, which does not have the aforementioned disadvantages.

I. Process Steps According to the Invention in the Preparation ofCompounds of the General Formula (I)

The preparation process according to the invention is characterized byvarious advantageous preparation steps and also intermediates.

The process according to the invention for the preparation of compoundsof the general formula (I) is characterized by at least one of thefollowing steps:

-   I.a). Alkylation of 4-nitrothiophenol in the presence of potassium    carbonate in N-methyl-pyrrolidinone (NMP) to give a    nitrophenyl-sulphide of the formula (I-1)

-   -   where X is Br, Cl, I, O—SO₂—CH₃ or O—SO₂-(4-methylphenyl)

-   I.b). Oxidative amination of the nitrophenyl-sulphide of the formula    (I-1) to give a trifluoroacetate-protected nitrophenyl-sulphilimine    of the formula (I-10)

-   I.c). Oxidation of the trifluoroacetate-protected    nitrophenyl-sulphilimine of the formula (I-10) to give a    trifluoroacetate-protected nitrophenyl-sulphoximine of the formula    (I-3) and subsequent deprotection to give a nitrophenyl-sulphoximine    of the formula (I-11)

I.d). Racemate cleavage of a nitrophenyl-sulphoximine of the formula(I-11) with the help of (+)-di-O-p-toluoyl-D-tartaric acid

-   -   where the R enantiomer of the nitrophenyl-sulphoximine of the        formula (I-11-R) is then released from the salts and the        trifluoroacetate protective group is inserted again to form the        R enantiomer of the trifluoroacetate-protected        nitrophenyl-sulphoximine of the formula (I-3-R),

-   I.e). Hydrogenation of trifluoroacetate-protected    nitrophenyl-sulphoximines of the formula (I-3-R) to give    trifluoroacetate-protected anilino-sulphoximines of the formula    (I-4-R) with an iron-doped palladium catalyst

-   I.f). Preparation of (2R,3R)-3-(benzyloxy)butan-2-ol (I-5-A) in a    two-stage process via (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane    (I-12-A), where the first stage is carried out with pyridinium    p-toluenesulphonate in toluene and then a diisobutylaluminium    hydride reduction takes place in toluene,

-   I.g). Coupling of (I-5-A) with    2,4-dichloro-5-trifluoromethylpyrimidine to give    4-{[(2R,3R)-3-(benzyloxy)butan-2-yl]oxy}-2-chloro-5-(trifluoromethyl)pyrimidine    (I-7-A) with Li bases in ethereal solvents

-   I.h). Preparation of benzenesulphonic acid salts of doubly protected    anilino-pyrimidines of the formula (I-8-R-BSA) by benzenesulphonic    acid-catalysed coupling of (I-7-A) and (I-4-R)

-   I.i). Cleaving off of the protective groups in benzenesulphonic acid    salts of doubly protected anilino-pyrimidines of the formula    (I-8-R-BSA) by hydrogenation with palladium on activated carbon and    hydrogen in methanol, and also by treatment with potassium carbonate    in methanol to give compounds of the formula (I)

Preparation Steps of the “North Half” of the Compounds According toFormula (I) I.a) Preparation of Nitrophenyl-Sulphides of the Formula(I-1)

One subject matter of the invention relates to the alkylation step of4-nitrophenol. The starting material (I-1) was prepared in accordancewith WO2010/046035A1 from cyclopropyl sulphide. The latter is notcommercially available in large amounts. We therefore switched to analkylation of commercially available 4-nitrothiophenol with alkylatingagents (X—R⁴) in the presence of an auxiliary base, where X is Br, Cl,I, O—SO₂—CH₃ or O—SO₂-(4-methylphenyl). Suitable bases are sodiumcarbonate, potassium carbonate or caesium carbonate, preferablypotassium carbonate. Suitable solvents are N,N-dimethylformamide,N-methylpyrrolidinone, dimethyl sulphoxide, N,N-dimethylacetamide,preferably N-methylpyrrolidinone.

Further subjects of the invention relate to the oxidative amination ofnitrophenyl-sulphides of the formula (I-1) to givetrifluoroacetate-protected nitrophenyl-sulphilimines of the formula(I-10) (FIG. 2) and the subsequent oxidation tonitrophenyl-sulphoximines of the formula (I-11) (FIG. 3).

I.b) Preparation of the Trifluoroacetate-ProtectedNitrophenyl-Sulphilimines of the Formula (I-10)

State of the Art for the Preparation of Sulphilimines

The aim was a direct amination of sulphides to give thetrifluoroacetate-protected sulphilimines, that can be readily used forpreparative purposes, using simple starting materials such as e.g.2,2,2-trifluoroacetamide (CF₃CONH₂). Carreira et al. (Org. Lett. 1999,1, 149-151) describes the Cu-catalyzed direct amination to givetrifluoroacetate-protected sulphilimines with the help of a lithiatedTFA-hydroxylamine, but this has to be prepared beforehand in two stagesand is not commercially available. This reaction takes placeenantioselectively with stoichiometric amounts of a nitride-Mn complex(Helv. Chim. Acta. 2002, 3773-3783).

Bolm et al. reports (Tetrahedron Letters 2005) that a direct metal-freeimination of sulphides is possible. p-Nitrophenylsulphonamide(nosylamide, Nos-NH₂) and (diacetoxyiodo)benzene (PhI(OAc)₂) areproposed, and nosyl-protected sulphilimines are obtained after refluxfor 16 h. However, these conditions are not very suitable for a scale-upsince the p-nitrophenylsulphonamide protective group can only be removedwith difficulty and (diacetoxyiodo)benzene is not commercially availablein large amounts.

Suitable oxidizing agents in the reaction according to the invention asin FIG. 2 are, inter alia, N-bromosuccinimide, iodine, sodiumhypobromide, 1,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide andtrichlorocyanuric acid in the presence of the bases caesium carbonate,potassium tert-butylate, sodium tert-butylate, aqueous sodium hydroxidesolution, sodium methanolate, sodium ethanolate, sodium hydride (NaH) inthe solvents methanol, dichloromethane, tetrahydrofuran/water,acetonitrile, acetonitrile/water, tetrahydrofuran (THF), propionitrile,methyl tert-butyl ether, 1,4-dioxane, chlorobenzene.

A preferred oxidizing agent is 1,3-dibromo-5,5-dimethylhydantoin.

Preferred solvent/base combinations are the combinationsacetonitrile/caesium carbonate, 1,4-dioxane/sodium hydride,dichloromethane/potassium tert-butylate, aceonitrile/sodium hydride,tetrahydrofuran/sodium hydride or methyl tert-butyl ether/sodiumhydride.

The desired reaction proceeds to completion at just 20° C. within a fewhours without adding a catalyst.

Compared to the routes known from the literature, the novel oxidativeamination, as shown in FIG. 2, gives rise to the following advantages:

-   -   it is possible to dispense with the expensive and potentially        explosion-hazardous (diacetoxyiodo)benzene and also with the        addition of metal salts;    -   barely any sulphoxide is formed and the reaction proceeds under        mild conditions at just 20° C. using commercially available        building blocks and reagents;    -   the trifluoroacetate group can be hydrolysed very easily (e.g.        potassium carbonate in methanol) and is therefore of high        preparative value.

It is not only nitrophenyl-sulphides of the formula (I-1) which can beaminated oxidatively according to step I.b). Furthertrifluoroacetate-protected sulphilimines can also be prepared in thisway.

Table 1 shows further sulphilimines accessible using this process step.

TABLE 1

Substance Sulphilimine Yield 1

81% 2

88% 3

80% 4

75% 5

74% 6

71%

I.c) Preparation of Nitrophenyl-Sulphoximines of the Formula (I-11)

The oxidation of the trifluoroacetate-protected nitrophenyl-sulphilimine(I-10) to give the nitrophenyl-sulphoximine (I-11) preferably takesplace with potassium peroxomonosulphate (Oxone®) as oxidizing agent.

The desired oxidation proceeds particularly rapidly in the basic pHrange. Under these conditions, the trifluoroacetate group is cleaved offat the same time, meaning that the deprotection step which optionallyfollows can be carried out as a one-pot reaction.

The reaction is particularly preferably carried out in a methanol/watermixture and tetramethylenesulphone (sulpholane) is added as solubilitypromoter. The potassium peroxomonosulphate (Oxone®) is added in portionsand the pH is adjusted to pH 10 after each dosing step.

I.d) Racemate Resolution of Nitrophenyl-Sulphoximines of the Formula(I-11)

A further subject matter of the present invention relates to theracemate resolution of nitrophenyl-sulphoximines of the formula (I-11).

The racemate resolution is based on the following step:

Surprisingly, it has been found, for example for thenitrophenyl-sulphoximine of the formula (I-11-A) that, using(+)-di-O-p-toluoyl-D-tartaric acid, a ratio of the enantiomers of 95:5in the crystallizate is obtained. Solvents which can be used areacetonitrile, propionitrile or toluene. Preference is given toacetonitrile or propionitrile.

The crystallization process can be integrated into the preparationprocess by cleaving off the trifluoroacetate protective group in (I-3)with potassium carbonate in methanol, and reacting the crudenitrophenyl-sulphoximine (I-11) with the (+)-di-O-p-toluoyl-D-tartaricacid to give (I-11-R-D-Tol-Tart.).

The toluoyl-D-tartaric acid is removed from the salt by basic extractionand the optically active nitrophenyl-sulphoximine of the formula(I-11-R) can be protected in the one-pot process with trifluoroaceticanhydride in the presence of triethylamine to give (I-3-R).

I.e) Hydrogenation of Trifluoroacetate-ProtectedNitrophenyl-Sulphoximines of the Formula (I-3-R) to GiveTrifluoroacetate-Protected Anilino-Sulphoximines of the Formula (I-4-R)

A further subject matter of the invention relates to the hydrogenationof trifluoroacetate-protected nitrophenyl-sulphoximines (I-3-R) to givetrifluoroacetate-protected anilino-sulphoximines of the formula (I-4-R)in the presence of an iron-doped palladium catalyst.

The reduction of the nitro group in the compound (I-3-R) into thecorresponding aniline (I-4-R) takes place efficiently by a hydrogenationwith immobilized palladium catalysts. Preference is given to iron-dopedpalladium catalysts on carbon. Solvents which can be used are methanol,ethanol, isopropanol, tetrahydrofuran or acetic acid. Preference isgiven to methanol.

Preparation Steps of the “South Half” of Compounds of the Formula (I)I.f) Preparation of (R,R)-dimethyldioxolane (I-12-A) and(R,R)-benzylbutanediol (I-5-A)

A further subject matter of the present invention relates to thepreparation of (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane (I-12-A) and(2R,3R)-3-(benzyloxy)butan-2-ol (I-5-A) for the “south half” ofcompounds of the formula (I).

According to WO2010/046035A1, the commercially available(R,R)-butane-2,3-diol is converted using benzyl chloride in one stage tothe monobenzylated (I-5-A). Since, as is expected, the conversion doesnot proceed selectively to give the mono compound, the reaction mixturehas to be purified by means of chromatography and the yields aretherefore <50%.

As an alternative, a two-stage process has been presented (Bioorg. Med.Chem. Lett. 2006, 16, 186-190).

One subject matter of the invention is the clarification of theexperimental conditions for a complete conversion, and also a simpleisolation and purification which are suitable for an industrial scale.The intermediate (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane (I-12-A) isobtained in a suitable manner by reacting benzaldehyde dimethyl acetaland an excess of (2R,3R)-butane-2,3-diol in the presence of pyridiniump-toluenesulphonate in toluene as solvent. The reaction was complete at50° C. within 3 h, during which methanol should be distilled offcontinuously at reduced pressure.

In the course of the aqueous work-up, the excess diol was removed byextraction. The remaining toluenic phase can be used directly in thesubsequent stage.

For the subsequent reduction with diisobutylaluminium hydride (DIBAL), a1.5 M solution of diisobutylaluminium hydride in toluene was used at55-60° C. For the work-up, sodium sulphate decahydrate was metered inand the solvent was distilled off after filtration. This gave thecompound (I-5-A) in good purities and yields. The product can be used inthe subsequent stage without further purification.

I.g) Preparation of4-{[(2R,3R)-3-(benzyloxy)butan-2-yl]oxy}-2-chloro-5-(trifluoromethyl)pyrimidine(I-7-A)

The nucleophilic monosubstitution of a chlorine atom to givecommercially available 2,4-dichloro-5-trifluoromethylpyrimidinepreferably proceeds in the 2-position

It has surprisingly been found that the substitution can be steered tothe desired 4-position by varying the conditions. It has been shown thatLi bases in ethereal solvents at −30° C. produced good conversions and,in the best case, produced a ratio of 4-isomer/2-isomer of 1.2:1.Solvents which can be used are, for example, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, methyl tert-butyl ether, diisopropylether, n-dibutyl ether, 2-methyltetrahydrofuran or cyclopentyl methylether. Preference is given to tetrahydrofuran. Bases which can be usedare e.g. lithium hexamethyldisilazide, n-butyllithium, lithiumdiisopropylamide or lithium-2,2,6,6-tetramethylpiperidine. Preference isgiven to lithium hexamethyldisilazide. The temperature range is −78° C.to +20° C. The process step according to the invention was derived fromthis, and operates with lithium hexamethyldisilazide in tetrahydrofuranat −30° C. and produces the desired isomer (I-7-A) followingchromatography in yields of up to 46% and purities of >95% area.

Coupling of the north and south halves and preparation of the compoundsaccording to formula (I)

I.h) Preparation of Anilino-Pyrimidines of the Formula (I-8-R-BSA)

The two building blocks (I-7-A) and (I-4-R) are coupled to give (I-8-R).This reaction is acid-mediated. Suitable acids are, for example,hydrochloric acid, p-toluenesulphonic acid, benzenesulphonic acid,methanesulphonic acid. Preference is given to benzenesulphonic acid.

The free bases (I-8-R) are usually oils, which makes purification andalso storage more complicated. Surprisingly, it has been found that whenusing benzenesulphonic acid, the resulting benzenesulphonic acid salts(I-8-R-BSA) crystallize out of the reaction mixture. The salts(I-8-R-BSA) can be purified by crystallization and are storage-stable.

Alternatively, toluenesulphonic acid or methanesulphonic acid can beused.

I.i) Preparation of the Compounds of the Formula (I)

In the last two steps, the protective groups are cleaved off (FIG. 11).

The hydrogenation at atmospheric pressure takes place withpalladium/carbon and hydrogen in methanol within a few hours to give theintermediate of the formula (I-9-R-BSA).

The intermediate of the formula (I-9-R-BSA) can be further reacteddirectly to give the end stage. The cleaving off of the group can becompleted with potassium carbonate and the crystallization of the endstage takes place from ethyl acetate/n-heptane.

II. Intermediates

Further subjects of the present invention are the followingintermediates

-   II. a) Trifluoroacetate-protected nitrophenyl-sulphilimines of the    formula (I-10), in particular (I-10-A)

-   II. b) Nitrophenyl-sulphoximines of the formula (I-11-R), in    particular (I-11-A) and (I-11-A-R)

-   II. c) (R)-enantiomers of trifluoroacetate-protected    nitrophenyl-sulphoximines of the formula (I-3-R), in particular    (I-3-A-R)

-   II. d) Salts (I-11-R-D-Tol-Tart.) of the nitrophenyl-sulphoximines    of the formula (I-11-R) with (+)-di-O-p-toluoyl-D-tartaric acid, in    particular (I-11-A-R-D-Tol-Tart.)

-   I.e) Anilinopyrimidines of the formula (I-8-R-BSA), in particular    (I-8-A-R-BSA)

where R⁴ is in each case a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring.

I-A. Preparation of the Compound A Preparation of the “North Half” ofCompound A I-A.a) Preparation of cyclopropyl-nitrophenyl-sulphide(I-1-A)

In the first step of the reaction sequence, 4-nitrothiophenol isalkylated with bromocyclopropane in the presence of potassium carbonate.The desired reaction proceeds in N-methylpyrrolidinone (NMP) within 8-10h at a preferred temperature of 135° C.

The isolation of (I-1-A) was carried out by metering the reactionmixture on to ice-water, and the crude crystallizate was isolated with agood purity of typically 89-93 area % with a yield of 82-87%.

I-A.b) Preparation of the trifluoroacetate-protectedcyclopropyl-nitrophenyl-sulphilimine (I-10-A)

In the second step, an oxidative amination to give thetrifluoroacetate-protected cyclopropyl-nitrophenyl-sulphilimine (I-10-A)takes place.

In a broad screening, the conversion of thecyclopropyl-nitrophenyl-sulphide (I-1-A) into thetrifluoroacetate-protected cyclopropyl-nitrophenyl-sulphilimine (I-10-A)was investigated. Suitable oxidizing agents in the reaction according tothe invention as in FIG. 13 are N-bromosuccinimide,1,3-dibromo-5,5-dimethylhydantoin in the presence of the bases potassiumtert-butylate, sodium hydride in the solvents dichloromethane,tetrahydrofuran or acetonitrile. The desired reaction proceeds in atemperature window from 0-50° C., with 20° C. being preferred.

The oxidizing agents tested were 1,3-dibromo-5,5-dimethylhydantoin,N-chlorosuccinimide and trichlorocyanuric acid in the presence of thebases potassium tert-butylate, sodium tert-butylate, aqueous sodiumhydroxide solution, sodium hydroxide, sodium methanolate, sodium hydridein the solvents methanol, dichloromethane, tetrahydrofuran/water,acetonitrile, acetonitrile/water, tetrahydrofuran, propionitrile, methyltert-butyl ether, dioxane, chlorobenzene.

In the course of the reaction, the sodium hydride in tetrahydrofuran wasintroduced as initial charge and cyclopropyl-nitrophenyl-sulphide(I-1-A) was added dropwise with trifluoroacetamide. With cooling, asolution of 1,3-dibromo-5,5-dimethylhydantoin in tetrahydrofuran wasmetered in and the mixture was stirred at room temperature. Work-up isby reductive (sodium sulphite) means, and crystallization fromdiisopropyl ether/n-heptane was performed. This gave the product(I-10-A) in good yields and purities.

I-A.c) Preparation of 1-(cyclopropylsulphonimidoyl)-4-nitrobenzene(I-11-A)

The oxidation of the trifluoroacetate-protected nitrophenyl-sulphilimine((I-10-A)) to give 1-(cyclopropylsulphonimidoyl)-4-nitrobenzene (I-11-A)preferably takes place with potassium peroxomonosulphate (Oxone®) asoxidizing agent.

The reaction was carried out in a methanol/water mixture andtetramethylenesulphone (sulpholane) was added as solubility promoter.The potassium peroxomonosulphate (Oxone®) is added in portions and thepH is adjusted to pH 10 after each dosing step.

After 5 h, 99% conversion is already observed to the desired racemic1-(cyclopropylsulphonimidoyl)-4-nitrobenzene (I-11-A). Work-up is byaqueous (sodium sulphite) means and the product is crystallized from theorganic phase (methylene chloride) after drying over magnesium sulphatefrom n-heptane.

I-A.d) Racemate resolution of1-(cyclopropylsulphonimidoyl)-4-nitrobenzene (I-11-A)

The racemate resolution is based on the following step:

Surprisingly, it has been found that with (+)-di-O-p-toluoyl-D-tartaricacid in acetonitrile, a ratio of the enantiomers of at least 95:5 in thecrystallizate is obtained. The yields were 40-45%. Alternatively toacetonitrile, it is also possible to use propionitrile. The opticalpurity can be further improved by recrystallization from acetonitrile orpropionitrile.

The crystallization process can be integrated into the preparationprocess by cleaving off the trifluoroacetate protective group in (I-3-A)with potassium carbonate in methanol and reacting crudenitrophenyl-sulphoximine (I-11-A) with (+)-di-O-p-toluoyl-D-tartaricacid in acetonitrile to give (I-11-A-D-Tart.).

The optically active nitrophenyl-sulphoximine is released by basicextraction and then protected in the one-pot process withtrifluoroacetic anhydride in the presence of triethylamine to give(I-3-A-R).

The route to the trifluoroacetate-protected nitrophenyl-sulphoximine(I-3-A) described in WO2010/046035A1 produces the north building blockas racemate.

I-A.e) Hydrogenation to give the trifluoroacetate-protectedanilino-sulphoximine (I-4-A-R)

Conversion of the nitro group in the compound (I-3-A-R) to thecorresponding aniline (I-4-A-R) takes place via a hydrogenation withimmobilized palladium catalysts. A particularly clean product isobtained by using iron-doped palladium catalysts on carbon. Methanol ispreferred as solvent. The trifluoroacetate-protectedanilino-sulphoximine (I-4-A-R) can be isolated after crystallizationwith a yield of at least 88%.

Preparation of the “South Half” of Compound A

The construction of the south half of compound A takes place accordingto the invention as in I.g) and II).

Coupling of North and South Halves I-A.h) Preparation ofN-[(4-{[4-{[(2R,3R)-3-(benzyloxy)butan-2-yl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)(cyclopropyl)oxido-lambda⁶-sulphanylidene]-2,2,2-trifluoroacetamidebenzenesulphonic acid salt (I-8-A-R-BSA)

In the first step, the two building blocks (I-7-A) and (I-4-A-R) arecoupled to give (I-8-A-R). This reaction is acid-mediated. The free base(I-8-A-R) is an oil. Surprisingly, it has been found that when using1,4-dioxane as solvent, the resulting benzenesulphonic acid salt(I-8-A-R-BSA) crystallizes from the reaction mixture.

The crystallization can be completed with n-heptane, and the desiredN-[(4-{[4-{[(2R,3R)-3-(benzyloxy)butan-2-yl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)(cyclopropyl)oxido-lambda⁶-sulphanylidene]-2,2,2-trifluoroacetamideebenzenesulphonic acid salt is obtained in good yields. The salt(1-8.A-R-BSA) is crystalline and storable and it is isolated with atypical purity of ca. 90 area %.

I-A.i) Preparation of the Compound A

In the last two steps, the protective groups are cleaved off (FIG. 20).

The intermediate I-9-A-R-BSA was not isolated, but further reacteddirectly to give the end stage. The cleaving off of the trifluoroacetategroup was completed with potassium carbonate in methanol and thecrystallization of the end stage was performed from a mixture of ethylacetate/heptane.

7. Concordance

TABLE 2 Name Article name Structure IUPAC name MW I-1nitrophenyl-sulphide

I-1-A cyclopropyl- nitrophenyl-sulphide

1-(cyclopropylsulphanyl)-4- nitrobenzene 195.24 I-2 nitrophenyl-sulphoxide

I-3 trifluoroacetate- protected nitrophenyl- sulphoximine

I-3-R (R) enantiomer of the trifluoroacetate- protected nitrophenyl-sulphoximine

I-3-A-R (R) enantiomer of the trifluoroacetate- protected cyclopropyl-nitrophenyl- sulphoximine

N-[(R)-cyclopropyl(4- nitrophenyl)oxido-lambda⁶- sulphanylidene]-2,2,2-trifluoroacetamide 322.26 I-4 trifluoroacetate- protected anilino-sulphoximine

I-4-R (R) enantiomer of the trifluoroacetate- protected anilino-sulphoximine

I-4-A-R (R) enantiomer of the trifluoroacetate- protectedcyclopropyl-anilino- sulphoximine

N-[(R)-(4- aminophenyl)(cyclopropyl)oxido- lambda⁶-sulphanylidene]-2,2,2- trifluoroacetamide 292.28 I-5-A

(2R,3R)-3-(benzyloxy)butan-2-ol 180.25 I-6 protected hydroxyalkoxy-pyrimidine

I-7 protected CF₃ intermediate

I-7-A benzyl-protected CF₃ intermediate

4-{[(2R,3R)-3-(benzyloxy)butan-2- yl]oxy}-2-chloro-5-(trifluoromethyl)pyrimidine 360.77 I-8 doubly protectedanilinopyrimidines

I-8-R- BSA benzenesulphonic acid salt of doubly protectedanilinopyrimidines

I-8-A-R- BSA benzenesulphonic acid salt of doubly protectedcyclopropylanilino- pyrimidines

N-[(4-{[4-{[(2R,3R)-3- (benzyloxy)butan-2-yl]oxy}-5-(trifluoromethyl)pyrimidin-2- yl]amino}phenyl)(cyclopropyl) oxideo-lambda⁶-sulphanylidene]- 2,2,2-trifluoroacetamide benzenesulphonicacid salt (1:1) 774.76 I-9 singly protected anilinopyrimidines

I-9-R- BSA benzenesulphonic acid salt of singly protectedanilinopyrimidines

I-9-A-R- BSA benzenesulphonic acid salt of singly protectedcyclopropylanilino- pyrimidines

N-[cyclopropyl(4-{[4-{[(2R,3R)-3- hydroxybutan-2-yl]oxy}-5-(trifluoromethyl)pyrimidin-2- yl]amino}phenyl)oxido-lambda⁶-sulphanylidene]-2,2,2- trifluoroacetamide benzenesulphonic acidsalt (1:1) 684.64 I-10 trifluoroacetate- protected nitrophenyl-sulphilimine

I-10-A trifluoroacetate- protected cyclopropyl- nitrophenyl-sulphilimine

N-[cyclopropyl(4-nitrophenyl)- lambda⁴-sulphanylidene]-2,2,2-trifluoroacetamide 306.27 I-11 nitrophenyl- sulphoximine

I-11-R R enantiomer of the nitrophenyl- sulphoximine

I-11-A cyclopropyl- nitrophenyl- sulphoximine

1-(cyclopropylsulphonimidoyl)-4- nitrobenzene 226.26 I-11-A-R Renantiomer of the cyclopropyl- nitrophenyl- sulphoximine

1-(R-cyclopropylsulphonimidoyl)- 4-nitrobenzene 226.26 I-11-R-D-Tol-Tart. toluoyl-D-tartaric acid salt of the R- enantiomer ofnitrophenyl- sulphoximine

1-(R)- (cyclopropylsulphonimidoyl)-4- nitrobenzene I-11-A-R- D-Tol-Tart.toluoyl-D-tartaric acid salt of the R- enantiomer of cyclopropyl-nitrophenyl- sulphoximine

(2S,3S)-2,3-bis[(4- methylbenzoyl)oxy]succinic acid-1-(R-cyclopropylsulphonimidoyl)- 4-nitrobenzene (1:1) 612.62 I-12-A

(4R,5R)-4,5-dimethyl-2-phenyl-1,3- dioxolane 178.23 Compound A compoundA

(2R,3R)-3-{[2-{[4-(R- cyclopropylsulphonimidoyl)phenyl] amino}-5-(trifluoromethyl)pyrimidin-4- yl]oxy}butan-2-ol 430.45 Compound of theformula (I)

EXAMPLE Preparation of 1-(cyclopropylsulphanyl)-4-nitrobenzene (I-1-A)

A solution of 80 g (0.51 mol) of 4-nitrothiophenol (80%) in 400 ml ofN-methylpyrrolidinone (NMP) was added over the course of 30 min to asuspension of 92.6 g (0.67 mol) of potassium carbonate in 400 ml of NMP.The temperature increased during this to 30° C.

93.6 g (0.77 mol) of cyclopropyl bromide were added to the reactionmixture, which was stirred for 8 h at 135-140° C. The mixture was cooledto 20° C. and admixed with 4.0 g of activated carbon. The following werethen carried out: heating to 65° C., stirring for one hour, filteringand after-washing with 80 ml of NMP. The mixture was cooled to 20° C.and metered over the course of 1 h on to 3 l of water. Filtration wascarried out and the filter cake was washed three times with in each case400 ml of water. The mixture was then stirred with 800 ml of a 1 M aq.hydrochloric acid and filtered again, and the filter cake was washedthree times with in each case 400 ml of water. Finally, it was dried invacuo at 40° C., giving 86.6 g (86%) of the title compound (I-1-A) witha purity of 91.2 area %.

The crude material can be further purified. For this 90 g of the crudematerial are dissolved in 700 ml of n-heptane, heated to 65° C., ca. 400ml of n-heptane is distilled off and seed crystals are added whilecooling to 20° C. The mixture is stirred for one hour at 0-5° C. andfiltered, and the residue is washed with 100 ml of cold n-heptane. Afterdrying, 81 g of the title compound (I-1-A) with a purity of 100 area %are obtained.

NMR and MS analysis: Luecking, Ulrich; Krueger, Martin; Jautelat, Rolf;Siemeister, Gerhard. Preparation of pyrimidinylaminoarylsulphoximines ascyclin dependent kinase (CDK) and/or vascular endothelial growth factor(VEGF) inhibitors: WO 2005037800, page 105.

HPLC method A: Column Zorbax SB-Aq 150×3 mm, 3.5 μM; gradient: 0-20 minfrom 95% aq. phosphate buffer pH 2.4/5% acetonitrile to 20% aq.phosphate buffer pH 2.4/80% acetonitrile, flow: 0.5 ml/min, detection at210 nm, T=45° C.;

Retention time of (I-1-A) with method A: 16.7 min

Preparation ofN-[cyclopropyl(4-nitrophenyl)-lambda⁴-sulphanylidene]-2,2,2-trifluoroacetamide(I-10-A)

A solution of 11.5 g (58.9 mmol) of1-(cyclopropylsulphanyl)-4-nitrobenzene (I-1-A) and 10.0 g (88.4 mmol)of 2,2,2-trifluoroacetamide in 46 ml of tetrahydrofuran (THF) wasmetered at 0-5° C. over the course of 30 min into a suspension of 2.1 g(53 mmol) of sodium hydride (60% in mineral oil) in 50 ml oftetrahydrofuran.

A solution of 25.3 g (88.4 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in86 ml of tetrahydrofuran was added to the reaction mixture at 20-25° C.over the course of 15 min and the mixture was after-stirred for 14 h.

For the work-up, 70 ml of a 25% strength sodium sulphite solution and140 ml of toluene were added. The organic phase was washed three timeswith in each case 140 ml of water, concentrated in vacuo to ca. 80 g,admixed with 40 ml of n-heptane and after-stirred for 1.5 h at 20° C.The following were carried out: filtration, washing twice with in eachcase 25 ml of n-heptane and drying in vacuo at 40° C. This gave 14.5 gof the title compound (I-10-A) with 100 area % purity. This correspondedto a yield of 80.8%.

Larger Scale:

A solution of 80.0 g (409.8 mmol) of1-(cyclopropylsulphanyl)-4-nitrobenzene (I-1-A) and 69.5 g (614.6 mmol)of 2,2,2-trifluoroacetamide in 320 ml of THF were metered in to asuspension of 14.8 g (368.8 mmol) of sodium hydride (60% in mineral oil)in 360 ml of THF at 0-5° C. over the course of 45 min.

A solution of 175.7 g (614.6 mmol) of 1,3-dibromo-5,5-dimethylhydantoinin 550 ml of THF was then added at 0-5° C. over the course of 45 min.The mixture was thawed to 20° C. and left to stand for 14 h. For thework-up, 560 ml of a 10% citric acid solution and 1.1 l of toluene wereadded. The organic phase was washed with 560 ml of a 25% sodium sulphitesolution and three times with in each case 650 ml of water. The organicphase was concentrated in vacuo to ca. 750 g and admixed with 525 g ofn-heptane. The following were carried out: after-stirring for 1 h atroom temperature, filtration with suction and washing with 50 ml of a1:1 mixture of toluene/heptane. Drying in vacuo gave 90.7 g (72% yield)of the title compound (I-10-A) with 99.1 area % purity.

HPLC method A: retention time for (I-10-A): 14.8 min.

MS (CI): [M+H]⁺=307, [M+NH₄]⁺=324

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.19 (m, 1H) 1.21-1.38 (m, 3H)3.03-3.15 (m, 1H) 8.13-8.23 (m, 2H) 8.42-8.54 (m, 2H).

Preparation of 1-(S-cyclopropylsulphonimidoyl)-4-nitrobenzene (I-11-A)

To a solution of 100.0 g (326.5 mmol) of (I-10-A) in 850 ml of methanol,130 ml of tetramethylensulphone (sulpholane) and 590 ml of water wereadded 341.2 g (555.1 mmol) of potassium peroxomonosulphate (Oxone®)spread over eight portions at 25° C. After each addition, the pH wasadjusted to pH 10 using a 47% aqueous potassium carbonate solution. Intotal, ca. 350 ml of potassium carbonate solution were used. Theconversion was complete after one hour at 25° C. 960 ml ofdichloromethane were added and the mixture was stirred for 1 h at 20° C.It was filtered with suction and the residue was washed twice with ineach case 400 ml of dichloromethane. The combined organic phase waswashed with 400 ml of a 10% aqueous sodium sulphite solution and fourtimes with in each case 1 l of water. After separating the phases,drying was carried out over magnesium sulphate and concentration to ca.450 g. 100 ml of n-heptane were added, and the mixture was concentratedin vacuo to ca. 400 ml and after-stirred for one hour at 0-5° C. It wasfiltered with suction and the residue was washed twice with in each case100 ml of cold n-heptane. Finally, the mixture was dried in vacuo at 40°C., giving 68.5 g (92.8%) of the title compound (I-11-A) with a purityof 100 area %.

HPLC method A: retention time for (I-11-A): 9.5 min

MS (CI): [M+H]⁺=227

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.86-1.06 (m, 3H) 1.15 (dt, J=9.96, 4.19Hz, 1H) 2.69-2.88 (m, 1H) 4.65 (s, broad, 1H) 8.15 (d, J=8.80 Hz, 2H)8.41 (d, J=8.56 Hz, 2H).

Preparation of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioicacid-N-[(R)-cyclopropyl(4-nitrophenyl)oxido-lambda⁶-sulphanylidene]-2,2,2-trifluoroacetamide(1:1)(I-11-A-R-D-Tol-Tart.)

At 20° C., 116.4 g (301.2 mmol) of di-p-toluoyl-D-tartaric acid wereadded to a suspension of 64.9 g (286.8 mmol) of (I-11-A) in 1.3 l ofacetonitrile and the mixture was stirred for 16 h at 20° C. The mixturewas filtered with suction and the residue was washed twice with in eachcase 90 ml of acetonitrile. It was dried in vacuo at 40° C. to dryness,giving 71.1 g of (I-11-A-R-D-Tol-Tart.) This corresponded to a yield of40.4%.

HPLC method A: retention time for (I-11-A-D-Tart): 9.6 min (36.2%) &14.7 min (63.8%).

HPLC method B (L159-16EE): Chiralpak IC (DAICEL) length: 250 mm,internal diameter: 4.6 mm, particle size: 5 μm, gradient: 1:1n-heptane/isopropanol isocratic; flow: 1.0 ml/min, detection at 252 nm,T=35° C.

Retention time for R enantiomer: 9.3 min; retention time for Senantiomer: 8.4 min; Enantiomer excess (ee): 99.6%.

MS (ES+): [M+H]⁺=227; MS (ES−): [M−H]⁻=385

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91-1.06 (m, 3H) 1.10-1.20 (m, 1H) 2.41(s, 6H) 2.72-2.84 (m, 1H) 4.64 (s, broad, 1H) 5.82 (s, 2H) 7.40 (d,J=8.07 Hz, 4H) 7.90 (d, J=8.07 Hz, 4H) 8.09-8.20 (m, 2H) 8.33-8.52 (m,2H) 13.85 (s, broad, 2H).

Preparation ofN-[(R)-cyclopropyl(4-nitrophenyl)oxido-lambda⁶-sulphanylidene]-2,2,2-trifluoroacetamide(I-3-A-R)

A solution of 72.1 g (117.7 mmol) of (I-11-A-R-D-Tol-Tart.) in 720 ml ofdichloromethane was stirred for 60 min with a solution of 24.4 g ofpotassium carbonate in 350 ml of water at 20° C. The aqueous phase wasextracted with 360 ml of dichloromethane and the combined organic phasewas washed with 720 ml of water and dried over magnesium sulphate. Themixture was filtered and the filtrate was admixed with 49 ml (353.1mmol) of triethylamine and then with 49.9 ml (353.1 mmol) oftrifluoroacetic anhydride over the course of 40 min at 20-25° C. It wasafter-stirred for 10 min and then added to 1.1 l of a saturated sodiumhydrogen carbonate solution. After separating the phases, washing with1.0 l of water was carried out, followed by drying over magnesiumsulphate, and the solvent was distilled off in vacuo. The residue wastaken up in 120 ml of isopropanol and the resulting suspension wasstirred for 1 hour at 0-5° C. It was filtered and the residue was washedtwice with in each case 30 ml of cold isopropanol. It was dried in vacuoat 40° C., giving 27.3 g (75%) of (I-3-A-R.).

HPLC method A: retention time for (I-3-A-R): 16.4 min (99.6%).

HPLC method C (L159-10EE): Chiralpak IC (DAICEL) length: 250 mm,internal diameter: 4.6 mm, particle size: 5 μm, gradient: 1:1n-heptane/ethanol isocratic; flow: 1.0 ml/min, detection at 240 nm,T=35° C.

Retention time for R enantiomer (I-3-A-R): 4.5 min; retention time for Senantiomer: 3.7 min; Enantiomer excess (ee): 100%.

MS (DCI): [M+H]⁺=323, [M+NH₄]⁺=340

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.11-1.29 (m, 1H) 1.36-1.52 (m, 2H)1.74-1.88 (m, 1H) 2.69-2.89 (m, 1H) 8.14 (d, J=8.80 Hz, 2H) 8.47 (d,J=8.80 Hz, 2H).

Preparation ofN-[(R)-(4-aminophenyl)(cyclopropyl)oxido-lambda⁶-sulphanylidene]-2,2,2-trifluoroacetamide(I-4-A-R)

A suspension of 40.0 g (124.1 mmol) of (I-3-A-R) and 10.0 g of palladiumon carbon (Pd/C: 5% Pd, 1% Fe, 55% water) in 800 ml of methanol washydrogenated for seven hours at 2.5 bar. The mixture was filtered overkieselguhr and after-washed twice with in each case 200 ml of methanol.The filtrate was concentrated in vacuo and then 800 ml of water wereadded. The mixture was stirred for one hour, filtered and washed twicewith in each case 400 ml of water. The crystals were dried in vacuo at40° C. This gave 33.4 g (292.3 mmol) of the desired aniline (I-4-A-R).This corresponded to a yield of 92%.

HPLC method A: retention time for (I-4-A-R): 14.4 min (96.1%).

HPLC method C: retention time for R enantiomer (I-4-A-R): 13.7 min;retention time for S enantiomer: 12.2 min; enantiomer excess (ee): 100%.

MS (DCI): [M+H]⁺=293, [M+NH₄]⁺=310

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.16 (m, 1H) 1.17-1.40 (m, 2H)1.56-1.71 (m, 1H) 2.74 (tt, J=7.79, 4.92 Hz, 1H) 4.33 (br. s., 2H)6.67-6.79 (m, 2H) 7.58-7.74 (m, 2H).

Preparation of (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane (I-12-A)

A solution of 300 g (3.33 mol) of 2R,3R-butanediol, 422 g (2.78 mol) ofbenzaldehyde dimethyl acetal and 7.0 g (27.7 mmol) of pyridiniump-toluenesulphonate in 1.2 l of toluene was heated to 50° C. At 600-800mbar, ca. 400 ml of distillate were taken off over the course of 3hours. It was cooled and the reaction mixture was added to 500 ml of a 1M sodium hydroxide solution. The phases were separated and the organicphase was washed twice with in each case 500 ml of water. The organicphase was dried azeotropically, with ca. 250 ml of toluene beingdistilled off.

The product obtained in this way in toluene (1061 g) was used directlyin the next stage. For the analysis, a part amount was evaporated todryness.

The preparation of the compound (I-12-A) can inter alia also take placein accordance with the literature (Chemistry Letters (1995), 4, 263-4;Journal of Organic Chemistry (2003), 68(9), 3413-3415, Tetrahedron(1989), 45(2), 507-16; Journal of Organic Chemistry (2005), 70(20),8009-8016; Bioorganic & Medicinal Chemistry Letters (2006), 16(1),186-190; Journal of Organic Chemistry (1999), 64(20), 7594-7600).

GC method A: Column RTX-50 (fused silica, 100% methylphenylpolysiloxane)

length: 30 m, internal diameter: 0.32 mm, film thickness: 1.0 μm; flow:3 ml/min; carrier gas hydrogen; detector FID 320° C., injectortemperature 280° C.; analysis program: T=80° C., holding time 2 min,heating rate 10° C./min up to T=300° C., holding time 6 min.

Retention time (I-12-A): 12.1 min (98%), toluene 3.3 min.

MS (DCI): [M+H]⁺=179

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30-1.35 (m, 3H) 1.36-1.41 (m, 3H)3.74-3.87 (m, 2H) 5.94 (s, 1H) 7.32-7.41 (m, 3H) 7.49 (dd, J=7.70, 1.83Hz, 2H).

Preparation of (2R,3R)-3-(phenylmethoxy)-2-butanol (I-5-A)

The toluenic solution of (I-12-A) obtained from the previous stage wasdivided and further reacted in two batches:

530 g of the (I-12-A) solution were diluted with 500 ml of toluene,heated to 55° C. and admixed over the course of one hour with 2.2 l of a1.5 M diisobutylaluminium solution in toluene. The mixture was stirredfor three hours at 50-60° C. The reaction mixture was added over thecourse of one hour at 20-25° C. to a suspension of 500 g of sodiumsulphate decahydrate in 500 ml of toluene. Filtration was carried out,followed by after-washing ten times with in each case 500 ml of toluene.The combined organic phase was filtered over kieselguhr and the solventwas distilled off in vacuo. This gave 230 g (1.27 mol) of (I-5-A) in apartial conversion. This corresponded to a yield of ca. 76% over twostages.

The preparation of the compound (I-5-A) can inter alia also take placein accordance with the literature:

Bioorganic & Medicinal Chemistry Letters (2006), 16(1), 186-190; EP1291336A2; Journal of the American Chemical Society (1997), 119(19),4541-4542; Journal of Organic Chemistry (1990), 55(10), 3129-37.

HPLC method A: Retention time (I-5-A): 12.5 min (97.4%).

MS (EI+): [M+H]⁺=181

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (t, J=5.99 Hz, 6H) 2.77 (d,J=2.69 Hz, 1H) 3.25-3.36 (m, 1H) 3.61 (quind, J=6.54, 6.54, 6.54, 6.54,2.69 Hz, 1H) 4.43 (d, J=11.49 Hz, 1H) 4.66 (d, J=11.49 Hz, 1H) 7.26-7.38(m, 5H).

Preparation of4-{[(2R,3R)-3-(benzyloxy)butan-2-yl]oxy}-2-chloro-5-(trifluoromethyl)-pyrimidine(I-7-A)

At −35° C. and over the course of 30 min, 680 ml of a 1 M lithiumhexamethyl disilazide were metered into a solution of 140.4 g (647.3mmol) of 2,4-dichloro-5-(trifluoromethyl)pyrimidine and 122.5 g (679.6mmol) of (I-5-A) in 1.0 l of THF. The mixture was stirred for threehours at −30° C. It was heated to 0° C. and admixed with 1.0 l of waterover the course of 15 min. 1.0 l of acetic ester was added, the phaseswere separated and the aqueous phase was extracted with 300 ml of aceticester. The combined organic phase was concentrated by evaporation invacuo to a volume of ca. 1.5 l and washed with 1.0 l of water. It wasdried over sodium sulphate, filtered with suction over kieselguhr andevaporated in vacuo. This gave 238.4 g of the crude product as a brownoil. A second batch on the same scale produced a further 236 g of crudeproduct.

Both batches were combined and dissolved in 470 ml of heptane/aceticester 1:1. The mixture was filtered with suction over silica gel 60 andwashed twice with in each case 1.0 l of acetic ester. The combinedfiltrates were filtered over kieselguhr and dried over magnesiumsulphate, and the solvents were distilled off in vacuo. The residue waschromatographed over 15 kg of silica gel 60 with n-heptane/acetic ester15:1. This gave 171 g of (I-7-A) (35%) and 63 g of a mixed fractionwhich still contained 58 area % (I-7-A).

HPLC method A: Retention time (I-7-A) (4-isomer) 21.6 min (95%);retention time of the 2-isomer: 21.0 min

MS (ES−API): [M+H]⁺=361

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (d, J=6.36 Hz, 3H) 1.32 (d, J=6.36Hz, 3H) 3.74 (quin, J=6.17 Hz, 1H) 4.46 (d, J=11.98 Hz, 1H) 4.61 (d,J=11.98 Hz, 1H) 5.44 (quin, J=6.24 Hz, 1H) 7.11-7.46 (m, 5H) 8.85 (s,1H).

Preparation ofN-[(4-{[4-{[(2R,3R)-3-(benzyloxy)butan-2-yl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)(cyclopropyl)oxido-lambda⁶-sulphanylidene]-2,2,2-trifluoroacetamidebenzenesulphonic acid salt (1:1) (I-8-A-R-BSA)

A suspension of 52.0 g (144 mmol) of (I-7-A), 42.1 g (144 mmol) of(I-4-A-R) and 22.8 g (144 mmol) of benzenesulphonic acid in 842 ml ofdioxane was stirred for 16 h at 20° C. The mixture was then heated at55-60° C. for 19 hours. For the isolation, it was admixed at 20° C. withseed crystals and diluted with 1.68 l of n-heptane. It was stirred forone hour, filtered with suction, washed with 240 ml of dioxane/n-heptane(1:1) and with 240 ml of n-heptane. It was dried to constant weight invacuo at 40° C. This gave 113.7 g (100%) of the desired product as beigecrystals.

HPLC method A: Retention time (I-8-A-R-BSA) 22.3 min (94%); retentiontime for the already partially deprotected trifluoroacetate cleavageproduct 19.1 min (2.4%).

MS (ES+): [M+H]⁺=617

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (m, 2H) 1.19 (m, 3H) 1.34 (m, 3H),1.45 (m, 1H) 3.38 (m, 1H) 3.77 (m, 1H) 4.49 (d, 1H) 4.60 (d, 1H) 5.52(m, 1H) 7.30 (m, 7H) 7.60 (m, 2H) 7.92 (m, 2H) 8.09 (m, 2H) 8.63 (m, 1H)10.71 (m, 1H).

Preparation of(2R,3R)-3-{[2-{[4-(S-cyclopropylsulphonimidoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]oxy}butan-2-ol(Compound A)

Hydrogen was bubbled through a suspension of 120 g of (I-8-A-R-BSA) and60 g of 10% Pd/C in 640 g of methanol for 6 h at atmospheric pressure.Washing was carried out over kieselguhr and twice with in each case 100g of methanol. 53 g of potassium carbonate were added to the filtrateand the mixture was stirred for 1 h at 20° C.

For the work-up, 900 g of water and 700 g of dichloromethane were added.The aqueous phase was extracted with 700 g of dichloromethane and thecombined organic phases were washed with 900 g of water and dried oversodium sulphate. Filtration was carried out, followed by after-washingwith 400 g of dichloromethane. The solvent was distilled off in vacuo.The residue was dissolved in 10 g of acetic ester and admixed with 125 gof n-heptane. The mixture was stirred for 10 min at 20° C. and admixedagain with 125 of n-heptane. The following were carried out, stirringfor two hours at 20° C., filtration, washing with a mixture of n-heptane(70 g)/acetic ester (45 g) and with 100 g of n-heptane. Drying wascarried out in vacuo at 30° C. to constant mass. This gave 47 g (69%) ofthe target compound.

HPLC method A: Retention time compound A 14.24 min (100%).

MS (ESI⁺): [M+H]⁺=431

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.92 (m, 3H) 1.10 (m, 4H) 1.30 (d, 3H)2.62 (m, 1H) 3.85 (m, 1H) 4.08 (s, 1H) 4.91 (d, 1H) 5.31 (m, 1H) 7.83(d, 2H) 7.94 (d, 2H) 8.59 (s, 1H) 10.50 (m, 1H).

1. Process for the preparation of compounds of the general formula (I)

in which R⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring,characterized by at least one of the following steps: I.a). Alkylationof 4-nitrothiophenol in the presence of potassium carbonate inN-methyl-pyrrolidinone (NMP) to give a nitrophenyl-sulphide of theformula (I-1)

where X is Br, Cl, 1,0-SO₂—CH₃ or O—SO₂-(4-methylphenyl), I.b).Oxidative amination of the nitrophenyl-sulphide of the formula (I-1) togive a trifluoroacetate-protected nitrophenyl-sulphilimine of theformula (I-10)

I.c). Oxidation of the trifluoroacetate-protectednitrophenyl-sulphilimine of the formula (I-10) to give atrifluoroacetate-protected nitrophenyl-sulphoximine of the formula (I-3)and subsequent deprotection to give a nitrophenyl-sulphoximine of theformula (I-11)

I.d). Racemate cleavage of a nitrophenyl-sulphoximine of the formula(I-11) with the help of (+)-di-O-p-toluoyl-D-tartaric acid

where the R enantiomer of the nitrophenyl-sulphoximine of the formula(I-11-R) is then released from the salts and the trifluoroacetateprotective group is inserted again to form the R enantiomer of thetrifluoroacetate-protected nitrophenyl-sulphoximine of the formula(I-3-R), I.e). Hydrogenation of trifluoroacetate-protectednitrophenyl-sulphoximines of the formula (I-3-R) to givetrifluoroacetate-protected anilino-sulphoximines of the formula (I-4-R)with an iron-doped palladium catalyst

I.f). Preparation of (2R,3R)-3-(benzyloxy)butan-2-ol (I-5-A) in atwo-stage process via (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane(I-12-A), where the first stage is carried out with pyridiniump-toluenesulphonate in toluene and then a diisobutylaluminium hydridereduction takes place in toluene,

I.g). Coupling of (I-5-A) with 2,4-dichloro-5-trifluoromethylpyrimidineto give4-{[(2R,3R)-3-(benzyloxy)butan-2-yl]oxy}-2-chloro-5-(trifluoromethyl)pyrimidine(I-7-A) with Li bases in ethereal solvents

I.h). Preparation of benzenesulphonic acid salts of doubly protectedanilino-pyrimidines of the formula (I-8-R-BSA) by benzenesulphonicacid-catalysed coupling of (I-7-A) and (I-4-R)

I.i). Cleaving off of the protective groups in benzenesulphonic acidsalts of doubly protected anilino-pyrimidines of the formula (I-8-R-BSA)by hydrogenation with palladium on activated carbon and hydrogen inmethanol, and also by treatment with potassium carbonate in methanol togive compounds of the formula (I)


2. Process according to claim 1, where, in step I.b)1,3-dibromo-5,5-dimethylhydantoin is used as oxidizing agent andtrifluoroacetamide is used as reagent.
 3. Process according to claim 1,where, in step I.c), the oxidation takes place with potassiumperoxomonosulphate (Oxone®).
 4. Process according to claim 1, where, instep I.d), the nitrophenyl-sulphoximine of the formula (I-11) iscrystallized with (+)-di-O-p-toluoyl-D-tartaric acid in acetonitrile orpropionitrile.
 5. Process according to claim 1, where, in step I.g), thelithium base used is lithium hexamethyldisilazide and the etherealsolvent used is tetrahydrofuran.
 6. Intermediates of the formula (I-10)and (I-10-A)

where R⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring. 7.Intermediates of the formula (I-11-R), (I-11-A) and (I-11-A-R)

where R⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring. 8.Intermediates of the formula (I-3-R) and (I-3-A-R)

where R⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring.
 9. Salts ofthe formula (I-11-R-D-Tol-Tart.) of nitrophenyl-sulphoximines of theformula (I-11-R) with (+)-di-O-p-toluoyl-D-tartaric acid and the salt ofthe formula (I-11-A-R-D-Tol-Tart.)

where R⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring. 10.Intermediates of the formula (I-8-R-BSA) and (I-8-A-R-BSA)

where R⁴ is a C₁-C₆-alkyl group or a C₃-C₇-cycloalkyl ring.